HCV Research and News

January 28, 2011

Vitamins in the treatment of chronic viral hepatitis

Br J Nutr. 2011 Jan 24:1-8. [Epub ahead of print]

Fiorino S, Conti F, Gramenzi A, Loggi E, Cursaro C, Di Donato R, Micco L, Gitto S, Cuppini A, Bernardi M, Andreone P.

Operative Unit of Internal Medicine, Budrio Hospital, Budrio, BO, Italy.

Abstract

Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related chronic infections represent a major health problem worldwide. Although the efficacy of HBV and HCV treatment has improved, several important problems remain. Current recommended antiviral treatments are associated with considerable expense, adverse effects and poor efficacy in some patients. Thus, several alternative approaches have been attempted. To review the clinical experiences investigating the use of lipid- and water-soluble vitamins in the treatment of HBV- and HCV-related chronic infections, PubMed, the Cochrane Library, MEDLINE and EMBASE were searched for clinical studies on the use of vitamins in the treatment of HBV- and HCV-related hepatitis, alone or in combination with other antiviral options. Different randomised clinical trials and small case series have evaluated the potential virological and/or biochemical effects of several vitamins. The heterogeneous study designs and populations, the small number of patients enrolled, the weakness of endpoints and the different treatment schedules and follow-up periods make the results largely inconclusive. Only well-designed randomised controlled trials with well-selected endpoints will ascertain whether vitamins have any role in chronic viral hepatitis. Until such time, the use of vitamins cannot be recommended as a therapy for patients with chronic hepatitis B or C.

PMID: 21255469 [PubMed - as supplied by publisher]

Source

Women Experience Higher Rates of Adverse Events during Hepatitis C Virus Therapy in HIV Infection: A Meta-analysis

Debika Bhattacharya, MD; T. Umbleja, MS; F. Carrat, MD, PhD; R. T. Chung, MD; M. G. Peters, MD; F. Torriani, MD; J. Andersen, PhD; J. S. Currier, MD, MSc

Posted: 01/27/2011; J Acquir Immune Defic Syndr. 2010;55(2):170-175. © 2010 Lippincott Williams & Wilkins

Abstract and Introduction

Abstract

Background: In HIV/ hepatitis C virus (HCV) coinfection, adverse events (AEs) during HCV therapy account for 12%-39% of treatment discontinuations. It is unknown whether sex influences complications.

Methods: Meta-analysis to study the effect of sex and other predictors of AEs in 3 randomized trials, ACTG 5071, APRICOT, and ANRSHCO2-RIBAVIC of Interferon (IFN) and Pegylated IFN (PEG), both with and without Ribavirin, in HIV/HCV coinfection. Primary endpoints were AEs requiring treatment discontinuation (AETD) or first dose modification (AEDM). Multi-covariate stratified logistic regression was used to study predictors and assess interactions with sex.

Results: Twenty-one percent of 1376 subjects were women; 61% had undetectable HIV RNA; 14% were antiretroviral (ARV) therapy naive at entry; median CD4 was 485 cells per cubicmillimeter. Seventeen percent had an AETD and 50% AEDM; women had more AETD than men (24% vs. 16% P = 0.003) and AEDM (61% vs. 48% P < 0.0001). AETD and AEDM occurred earlier in women; but the types of AETD and AEDM were similar between sexes. Seventy-four percent of AETDs and 49% of AEDMs involved constitutional AEs; 18% of AETD depression; and 26% of AEDM neutropenia. We identified interactions with sex and body mass index (BMI) (P = 0.04, continuous) and nonnucleoside reverse transcriptase inhibitor (P = 0.03); more AETDs were seen in men with lower BMI (P = 0.01) and in women on nonnucleoside reverse transcriptase inhibitors (P = 0.009). More AEDMs were seen with PEG [odds ratio (OR) = 2.07]; older age (OR = 1.48 per 10 years); decreasing BMI (OR = 1.04 per kg/m2); HCV genotype 1, 4 (OR = 1.31); Ishak 5, 6 (OR = 1.42); decreasing Hgb (OR = 1.23 per g/dL); and decreasing absolute neutrophil count (1.04 per 500 cells/mm3). Interactions between sex and ARV-naive status (P = 0.001) and zidovudine (P = 0.001) were identified: There were more AEDMs in ARV-naive women (P = 0.06) and ARV-experienced men (P = 0.001) and higher AEDMs in women with zidovudine (P = 0.0002).

Conclusions: Although there was no difference in type of AE, AETD and AEDM were more frequent and occurred earlier in women. In women, ARV regimen may be an important predictor of AETDs during HCV therapy and should be explored as a predictor of AEs in HIV/HCV coinfection trials.

Introduction

HIV and hepatitis C virus (HCV) coinfection is common, with reported prevalences of 16%-33% in HIV-infected individuals in the United States.[1,2] Liver-related mortality is the leading cause of death among HIV-infected persons in the United States in the highly active antiretroviral therapy era.[3] When compared with HCV monoinfection, hepatitis C therapy is less effective in HIV- and HCV-coinfected individuals due, in part, to high rates of treatment discontinuation.[4–6] In HCV infection without HIV, the percentage of discontinuations secondary to adverse events (AEs) or laboratory abnormalities ranged from 7% to 21%,[7–9] whereas in HIV coinfection, treatment discontinuations occurred in 12%-39%.[4–6] Understanding the role of factors such as sex and its relationship with the development of adverse drug reactions will be critical to improving treatment outcomes in HIV and HCV coinfection.

In HCV monoinfection, women are more likely to experience anemia with interferon and ribavirin therapy[10] and may be more likely to develop depression.[11–13] In HIV infection, studies with nucleoside analogue therapy suggested that women were more likely to require dose modifications, to develop severe symptoms, and to experience AEs related to didanosine.[14,15] There is little known, however, about the sex differences in AEs during HCV therapy in HIV/HCV coinfection. Additionally, the relationship between female sex, AEs during therapy, and other factors potentially related to AEs such as body mass index (BMI) and antiretroviral (ARV) regimen have not been well described in HIV and HCV coinfection.

The aim of our study was to investigate whether female sex was associated with an increased incidence and/or more rapid onset of AEs requiring treatment modification or discontinuation. In addition, we examined whether factors such as ARV regimen and BMI were important in predicting AEs in women and men.

Methods

We performed a meta-analysis of the AIDS Clinical Trials Group (ACTG) A5071, AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT), and Agence Nationale de Recherches sur le SIDA (ANRS) HCO2-RIBAVIC HCV treatment studies in HIV/HCV coinfection, conducted by different clinical trial networks between 2000 and 2003. Subject-level data were obtained for each study. Only subjects who initiated HCV treatment were included in the analysis. Detailed inclusion criteria, study design, and criteria for treatment discontinuation and dose modifications are described in detail elsewhere.[4–6] In A5071, subjects were randomized to receive 180 μg of peginterferon alfa-2a weekly for 48 weeks and dose-escalated ribavirin or 6 million IU of interferon alfa-2a 3 times weekly for 12 weeks followed by 3 million IU 3 times weekly for 36 weeks with dose-escalated ribavirin.[5] Ribavirin was administered as 600 milligrams per day for 4 weeks, 800 milligrams per day for 4 weeks, and then 1000 milligrams per day for the remainder of the study. In APRICOT, subjects were randomized to peginterferon alfa-2a (180 μg/wk) plus ribavirin (800 mg/d), peginterferon alfa-2a plus placebo, or interferon alfa-2a (3 million IU 3 times a week) plus ribavirin (800 mg/d).[6] In RIBAVIC, subjects were randomized to 1.5 μg/kg peginterferon alfa-2b once a week or subcutaneous injections of 3 million units of interferon alfa-2b 3 times a week for 48 weeks. All subjects also received 800 mg of ribavirin daily.[4] Laboratory toxicities, signs and symptoms, and clinical events, excluding death, were considered AEs. The primary endpoints were adverse events requiring treatment discontinuation (AETD) or first dose modification (AEDM). The primary endpoints were decided a priori and were selected because identification of factors responsible for treatment discontinuations and drug dose modifications may lead to implications for patient selection and management before and during therapy. Because the present analyses used data on subject level, the overall results are weighted by study, giving the greatest weight to APRICOT (62% of the N = 1376 subjects) followed by ANRSHCO2-RIBAVIC (28%) and A5071 (10%).

Statistical Analysis

Breslow-Day tests were used to ensure that it was appropriate to combine estimates from the 3 studies. Cochran-Mantel-Haenszel tests stratified by study were used to test statistical significance of differences in categorical variables between 2 groups. Stratified Wilcoxon rank-sum tests were used to test the statistical significance of differences between 2 groups in continuous variables. Predictors of AETD and AEDM were examined using simple logistic regression models, stratified by study. In addition to sex, predictors considered in analysis were HCV treatment (pegylated interferon-containing vs. not); race (white vs. non-white); age (continuous); BMI (continuous); HCV genotype (1, 4 vs. other); baseline Ishak fibrosis score (1–4 vs. higher); baseline HCV RNA (<800,000 vs. ≥800,000 IU/mL); baseline HIV-1 RNA (detectable vs. undetectable per definition of each study); baseline CD4 cell count (<500 vs. ≥500 cells/mm3); ARV naive at baseline; stavudine use at baseline; zidovudine (AZT) use at baseline; ARV regimen at baseline, nucleoside reverse transcriptase inhibitors only; containing nonnucleoside reverse transcriptase inhibitors (NNRTI) but no protease inhibitor (PI); containing any PI; baseline absolute neutrophil count (ANC, continuous); baseline platelets (continuous); baseline hemoglobin (continuous); baseline alanine aminotransferase (continuous); and baseline aspartate aminotransferase (continuous). Variables and their interactions with sex that were significant at 0.2 significance level in simple stratified logistic regression were considered in multi-covariate logistic regression models, stratified by study.

Kaplan-Meier estimates were used to summarize time-to-event results. Log-rank tests stratified by study were used to compare times to event between men and women. Stratified Cox proportional hazards model were used to provide an estimate for the magnitude of sex effect. Because AETD and AEDM are competing risks, times to AETD and AEDM were also analyzed using the competing risk methods[16] (treating death, nonresponse, loss to follow-up (LFU), and other known reason (primarily administrative) for treatment discontinuation as competing risks. The results were very similar to the results from Kaplan-Meier and Cox proportional hazards models, and the conclusions on the effect of sex were the same in both analyses. Therefore, the results of standard Kaplan-Meier analysis along with Cox proportional hazards model are provided for simpler interpretation. Results were considered statistically significant if P < 0.05 (2 sided).

Results

One thousand three hundred seventy-six subjects were included in the analysis, 288 (21%) of whom were women; 133 (10%), 860 (62%), and 383 (28%) subjects were from A5071, APRICOT, and ANRSHCO2-RIBAVIC, respectively. Subjects from A5071 were more likely to be non-white (52%), older (median age 45 years), overweight, or obese (57%) and have HCV genotype 1 or 4 (80%) than the subjects from APRICOT (21%, 39 years, 39% and 68%) or from ANRSHCO2-RIBAVIC (5%, 39 years, 18% and 61%).

Overall, 67% of subjects were infected with HCV genotype 1 or 4, and 83% had Ishak fibrosis score <4 (Table 1). Treatment regimens included pegylated interferon and ribavirin in 40%, interferon and ribavirin in 39%, and pegylated interferon alone in 21%; 40% of men and 40% of women received pegylated interferon and ribavirin therapy. Seventeen percent of women and 13% of men were ARV naive (P = 0.16); 48% of women and 42% of men were on D4T-containing regimens (P = 0.11); 18% of women and 11% of men were on nucleoside reverse transcriptase inhibitor-only regimens (P = 0.004); 29% of women and 34% of men were on AZT-containing regimens (P = 0.15); and 26% of women and 28% of men were on NNRTI-containing regimens (P = 0.47).

Fifty-three percent of women vs. 67% of men completed study treatment as specified by the respective study protocol; 24% vs. 16% discontinued treatment early due to toxicities, 11% vs. 9% due to nonresponse, 9% vs. 6% due to other known reasons; 1 woman of 288 vs. 1 man of 1088 died, and 3% of both women and men were lost to follow-up (P = 0.002, stratified by study) (not shown in Table 1).

Adverse Events Requiring Treatment Discontinuation

Women were more likely to experience an AETD than men, 24% vs. 16% (P = 0.003). Primary etiologies of AETD among the 238 who experienced an AETD included constitutional or other symptoms in 176 (74%) and depression in 44 (18%). Discontinuation due to hematologic abnormalities was not common; anemia, thrombocytopenia, and neutropenia were involved in 5%, 5%, and 3% of the treatment discontinuations, respectively, and there was no difference observed by sex. In a post hoc analysis that examined detailed etiologies of AETD among the 176 subjects with constitutional or other symptoms, 68 (39%) included fever, fatigue, weight loss, or gastrointestinal symptoms; 42 (24%) neurologic or psychiatric side effects, and 15 (9%) elevations in hepatic transaminases or lactic acid. The type of AETD was similar between the 2 sexes.

Predictors of AETD

In simple stratified analysis, female sex [odds ratio (OR) = 1.63] was a predictor of AETD. In addition, older age and lower baseline hemoglobin were statistically significant and lower baseline BMI was a marginally significant risk factor of AETD (Table 2). There was no evidence of association between AETD and the other factors listed in Methods-Statistical Analysis. In multicovariate analysis, age (P < 0.0001) and interactions between sex and BMI (P = 0.04) and between sex and NNRTI (P = 0.03) were statistically significant (Table 2). Men with higher BMIs were less likely to experience AETD than men with lower BMIs (OR = 0.94). This association was not observed in women. Women on NNRTI-containing regimens were more likely to have an AETD than ARV-naive women or women on other ARV regimens (OR = 2.23), whereas in men, no association between NNRTI-containing regimen and AETD was observed. Of the 69 women with an AETD, depression was responsible for 16 of 69 AETDs (23%); women on NNRTI therapy were more likely to experience depression, 8 of 25 (32%) than those who were on other ARV or not on ARV 8 of 44 (18%); (P = 0.02).

Adverse Events Requiring Treatment Modification

Women were more likely to experience an AEDM than men, 61% vs. 48% (P < 0.0001). Neutropenia and anemia were the primary hematologic etiologies of AEDM, involved in 26% and 17% of the AEDMs, respectively, and 49% of AEDMs involved constitutional AEs, but the type of AEDM was similar in men and women. An analysis that examined only subjects who received pegylated interferon and ribavirin, the standard of care regimen, demonstrated similar results (not shown).

Predictors of AEDM

In simple stratified analysis, female sex was a predictor of AEDM (OR = 1.72). In addition, pegylated interferon-containing regimen; non-white race; older age; lower baseline BMI; HCV genotype 1 or 4; Ishak fibrosis score 5 or 6; CD4 cell count <500; ARV experienced; AZT use; and lower baseline ANC, Hgb, and alanine aminotransferase were statistically significant predictors of AEDM (Table 3). The other factors listed in the Methods-Statistical Analysis were not statistically significantly associated with AEDM. In multicovariate analysis, receipt of pegylated interferon therapy (OR = 2.07, P < 0.0001), increasing age (OR = 1.48 per 10 years), decreasing BMI (OR = 1.04 per kg/m2), HCV genotype 1, 4 (OR = 1.31), Ishak 5, 6 (OR = 1.42), decreasing ANC (OR = 1.04 per 500 cells/mm3), and decreasing Hgb (OR = 1.23 per g/dL) remained statistically significant (Table 3).

We also identified interactions between sex and ARV-naive status (P = 0.001) and between sex and AZT use (P = 0.001). Interestingly, ARV-naive women were more likely to experience AEDMs than ARV-experienced women (OR = 1.96, P = 0.06), but ARV-naive men were less likely to experience AEDMs (OR = 0.51, P = 0.001). In women, more AEDMs were seen with AZT compared with non-AZT regimens or no ARV (OR 3.56, P = 0.0002); but this association was not seen in men (P = 0.59). In a subgroup analysis examining etiologies of dose modifications in 175 women with AEDM, women on AZT-containing therapy were more likely to experience neutropenia and anemia: 20 of 67 (30%) vs. 21 of 108 (19%) (P = 0.12) and 23 of 67 (34%) vs. 13 of 108 (12%) (P = 0.0004), respectively.

Time to AETD and AEDM

Women discontinued therapy and required dose modification earlier than men. The Cox proportional hazards ratio for time to AETD was 1.54 (95% CI: 1.16 to 2.04) for women compared with men (P = 0.003), whereas the Cox proportional hazards ratio for time to AEDM was 1.43 (95% CI: 1.20 to 1.70) for women compared with men (P < 0.0001) (Fig. 1). The median time to AEDM was 24 weeks in women and 48 weeks in men. There was also a trend toward more rapid platelet decline in women; the median time to the lowest platelet level was 15.6 (12.1–18.1) vs. 18.1 (16.1–18.9) weeks (P = 0.05).

Figure 1. A, Sex effect on the Time to AE requiring treatment discontinuation. B, Sex effect on the Time to AE requiring first study treatment dose modification.

Discussion

In a meta-analysis of 3 large HIV/HCV coinfection trials, women were more likely to experience an AETD or AEDM during HCV therapy in HIV infection. However, the observed types of AEs were similar between sexes. Additionally, AETD and AEDM occurred earlier in women. When exploring the effect modification by sex, women on regimens containing an NNRTI without a PI experienced more AETD and women on AZT-containing regimens experienced more AEs requiring interferon or ribavirin dose modification.

This is the first study to demonstrate that HIV-infected women on hepatitis C therapy experience more AETDs. Although similar sex effects on treatment discontinuation were not reported in large trials of HIV-uninfected HCV-infected women receiving interferon and ribavirin therapy,[7–9] other hepatitis C monoinfection analyses have demonstrated that women experience some AEs (depression and anemia) more commonly than men.[10,11] The relatively lower proportion of women enrolled in the landmark registration trials[7–9] may have precluded analysis of sex effects and discontinuation rates.

When examining the HIV literature, our findings of higher treatment discontinuations in women are similar to some[17,18] but not all[14,19,20] studies in HIV infection. In the CASCADE collaboration, women were more likely to discontinue ARV therapy (HR = 1.61, 95% CI: 1.15 to 2.27),[17] whereas in the ICONA study group, women were twice as likely to discontinue treatment secondary to toxicity.[18] Conversely, 3 other studies did not find higher overall rates of treatment discontinuations among women.[14,19,20]

A sex effect on ARV modifications has also been noted in HIV studies; Currier et al[14] demonstrated that women were 1.25 times more likely to modify didanosine dosage. In HIV infection, women are also more likely to experience AEs while on therapy with descriptions of increased rates of rash and hepatitis with nevirapine[21] and lactic acidosis with nucleoside analogues.[22] The reasons for heightened rates of AEs in women are poorly understood. Differences in body weight and composition, renal clearance, cellular kinase activity, and P-glycoprotein activity may all play a role.

Our finding that women on NNRTI regimens were more likely to discontinue HCV therapy than men is in agreement with other studies examining ARV regimen discontinuation in HIV infection. Women were more likely to discontinue efavirenz (EFV)-based regimens with 38.8% (95% CI: 28.8% to 48.7%) stopping EFV by 48 weeks of treatment compared with 28.3% of men (95% CI: 23.4% to 33.2%).[23] In our analysis, among women with AETD, women receiving NNRTI-based regimens had more depression. This finding, along with the findings that women are more likely to have elevated plasma EFV concentrations[24] are more likely to have mood disorders[25] and may be more likely to experience depression while on interferon therapy,[11] raise the possibility that neuropsychiatric side effects from interferon and EFV-based regimens may be accentuated in women. These findings should be interpreted with caution in this study, however, as we did not have data on type of NNRTI regimen and the number of women on NNRTI regimens who discontinued was small.

The finding that women were more likely to have AEDMs with AZT-containing regimens and a subgroup analysis demonstrating that the majority of AEDM on AZT-containing regimens were hematologic are not unexpected. Women are at an increased risk of developing anemia during ribavirin therapy,[10] and our study suggests that AZT may also play a role in hematologic toxicities in women receiving ribavirin. In hepatitis C monoinfection trials, Sulkowski et al[10] found that the incidence of reaching a Hgb <10 g/dL was 4-fold higher in women, whereas an analysis of interferon alpha-2a trials also found that women were more likely to have anemia.[26] One study demonstrated higher levels of AZT in women,[27] suggesting a possible mechanism for the additive toxicity of ribavirin and AZT. Anderson et al found that women had significantly higher intracellular concentrations of AZT with a female to male ratio of 2:3. Interestingly, we did not find a statistically significant sex difference in the rates of anemia leading to treatment discontinuation; the respective rates were small among both men and women, suggesting that these AEs were well managed in this clinical trial setting.

We also found that older age was independently associated with the incidence of AETD and dose modification. This is supported by Sulkowski et al[10] who also found that older age was associated with hemoglobin decrease in hepatitis C monoinfection studies. The authors speculated that older age may impact hematopoietic reserves in bone marrow, leading to more bone marrow suppression than in younger subjects.[10]

One limitation of our analysis was the heterogeneity of treatment protocols. In ACTG 5071, ribavirin was dose escalated from 600 to 800 mg, and subjects who experienced severe AEs stopped therapy. This dose escalation, however, would only have masked severe AEs. Additionally, the 3 protocols included varying regimens of interferon and ribavirin, with 40% of individuals receiving combination therapy with pegylated interferon and ribavirin. Subgroup analyses on this group with combination therapy, however, demonstrated similar results to that of all regimens. Another limitation of the study included the extensive use of ARVs (AZT and stavudine) that are less common in clinical practice today. Newer more tolerable ARV regimens such as the nuclesos(t)ide transcriptase inhibitor combinations (ie, tenofovir/emtricitabine and abacavir/lamivudine), boosted atazanavir, and raltegravir may lead to a reduced rate of adverse reactions attributable to concomitant ARV and HCV therapy. Analyses of these newer regimens with hepatitis C therapy, and their interactions with sex, are needed. We also acknowledge the presence of competing risks such as LFU, death, nonresponse, and unknown reasons for discontinuation. Therefore, time to AETD and time to first dose modification, respectively, were also analyzed in the competing risks setting, treating death, nonresponse, LFU, and other known reason for treatment discontinuation as competing risks. The results were very similar to the results from Kaplan-Meier and Cox proportional hazards model, and the conclusions on the effect of sex were the same in both analyses. Competing risks may have also reduced the observed AEs and, if dropout secondary to competing risks was associated with covariates, then confounding may have been introduced. Finally, the overall numbers of women experiencing AETDs and AEDMs were low at 69 and 175, respectively, leading us to interpret the interactions and subgroup analyses, including comparisons of types of AEs between men and women, with caution.

In conclusion, women are more likely to experience AEs, leading to hepatitis C treatment dose modification and discontinuation in the setting of HIV/HCV coinfection. Women on NNRTI regimens were more likely to discontinue therapy, and women on AZT-containing regimens were more likely to require dose modifications, suggesting an important sex-mediated role of ARV regimen on the impact of AEs during hepatitis C therapy. ARV regimen may be an important predictor of treatment discontinuation and modification in women and should be further explored as predictors of AEs in HIV/HCV coinfection trials.

References

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6.Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351:438–450.

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14.Currier JS, Spino C, Grimes J, et al. Differences between women and men in adverse events and CD4+ responses to nucleoside analogue therapy for HIV infection. The Aids Clinical Trials Group 175 Team. J Acquir Immune Defic Syndr. 2000;24:316–324.

15.Moore RD, Fortgang I, Keruly J, et al. Adverse events from drug therapy for human immunodeficiency virus disease. Am J Med. 1996;101:34–40.

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Source

Scientific finding aids anti-HCV therapy

2011/01/28 18:04:59

Taipei, Jan. 28 (CNA) Taiwan's top research institute Academia Sinica announced new findings Friday on the hepatitis C virus (HCV) that could help refine anti-HCV therapies in the future.

The team, led by research fellow Steve Chen, found that autophagy, a condition in which cells digest themselves, plays an important role in HCV replication, a process linked to the spread of infection in the body, the institute said.

The study offers medical scientists a direction for seeking more effective drugs for hepatitis C sufferers, Chen said, adding that drugs developed to suppress autophagy can be effective in stopping the virus from multiplying in the host body.

The findings were published in the Jan. 4 issue of the Journal of Clinical Investigation.

Although there are six major genotypes of HCV, only two drugs -- interferon and ribavirin -- are currently used for hepatitis C patients, who sometimes do not respond well to the drugs, Chen said.

"We hope that by understanding the mechanism by which HCV works, we can find ways to curb it," he added.

"This is only the first step in a long journey to find an effective drug for treating HCV," he said. "More work still needs to be done in this field." (By Nancy Liu) ENDITEM/J

Source

January 27, 2011

The role of triple therapy with protease inhibitors in hepatitis C virus genotype 1 naïve patients

Figure 1. ILLUMINATE: Phase 3: response-guided therapy optimal for eRVR Patients. eRVR, extended rapid virological response; SVR, sustained virological response.

Figure 2. ADVANCE: Phase 3: 12-week duration telaprevir optimal. PEG-IFN, pegylated interferon; RBV, ribavirin; RVR, rapid virological response; SVR, sustained virological response; TVR, telaprevir.

The phase III clinical trial (SPRINT-2) evaluating BOC in over 1000 treatment-naïve patients was also recently completed. Equivalent to the SPRINT-1 study design, patients (two separate cohorts were enrolled; one African American and the other non) received 800 mg BOC three times daily in combination with PEG-IFN and weight-based RBV for 24 or 48 weeks. A lead-in strategy for 4 weeks with PEG-IFN and RBV was utilized in all investigational arms. In this study, 66% of the patients in the BOC 48-week treatment group and 63% of the patients in the response-guided therapy group achieved SVR respectively, compared with 38% of patients in the control group (18). Among the non-African American patients in the BOC 48-week treatment group, 69% achieved SVR, and 67% achieved SVR in the response-guided therapy, compared with 40% in the control SOC group. Among African American patients, 53% of patients in the 48-week treatment group and 42% of patients in the response-guided therapy group achieved SVR, compared with 23% in the control group. This data is less clear than TVR phase 3 studies on the utility of response-guided therapy in all genotype 1 populations and suggest that extending therapy may be beneficial in African Americans. Further details from this study will help clarify the importance of host factors in response-guided therapy durations. In the HCV SPRINT-2 study, the most common treatment-emergent adverse events reported for the BOC 48-week treatment group, BOC response-guided therapy group and control group, respectively, were: fatigue (57, 53 and 60%), headache (46, 46 and 42%), nausea (43, 48 and 42%), anaemia (49, 49 and 29%) and pyrexia (fever) (32, 33 and 33%). Treatment was discontinued because of anaemia in 2% of each of the BOC groups compared with 1% in the control group, although erythropoietin use was allowed to maintain RBV dosing. Overall treatment discontinuations from adverse events were 16 and 12% for the BOC groups, respectively, compared with 16% for the control group. The utility of erythropoietin in these patients is currently under investigation in another phase 3 trial.

Conclusion

In conclusion, clinical trials have shown that the addition of protease inhibitors to standard therapy results in potent viral suppression and shortened duration of therapy. SVR rates approaching 75% can now be anticipated for genotype 1 patients, which should lead to increased treatment opportunities for many HCV populations. However, new issues of viral resistance and increased adverse events will increase the importance of close medical management. A new era of DAA is upon us and offers new hopes for HCV-infected patients.

Conflicts of interest

David Nelson has received research funding and is on advisory boards or a consultant for Vertex, Merck, Genentech, Pharmassett, Bayer-Onyx and GSK. He has received research funding from BMS, Gilead and Tibotech and is a consultant for Abbott.

References

1 Armstrong GL, Wasley A, Simard EP, et al. The prevalence of Hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006; 144: 705–14.

2 Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002; 36: S35–46.

3 Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology 2002; 36: S47–56.

4 Verna EC, Brown RS. Hepatitis C and liver transplantation: enhancing outcomes and should patients be retransplanted. Clin Liver Dis 2008; 12: 637–59.

5 Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010; 138: 513–21.

6 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic Hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.

7 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with Interferon alfa-2b plus ribavirin for initial treatment of chronic Hepatitis C: a Randomised Trial. Lancet 2001; 358: 958–65.

8 Asselah T, Benhamou Y, Marcellin P. Protease and polymerase inhibitors for the treatment of hepatitis C. Liver Int 2009; 29 (Suppl. 1): 57–67.

9 McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with Peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827–38.

10 Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–50.

11 Everson GT, Dusheiko GM, Ferenci P, et al. Telaprevir, peginterferon alfa-2a and ribavirin improved rates of sustained virologic response (SVR) in ‘difficult-to-cure’ patients with chronic Hepatitis C (CHC): a pooled analysis from the PROVE1 and PROVE2 trials. Hepatology 2009; 50: 1565.

12 Marcellin P, Forns X, Goeser T, et al. Virologic analysis of patients receiving telaprevir administered q8h or q12h with Peginterferon-alfa-2a or -alfa-2b and ribavirin in treatment-naïve patients with genotype 1 hepatitis: study C208. Hepatology 2009; 50: 194.

13 Kwo P, Lawitz E, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376: 705–16.

14 Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007; 132: 1767–77.

15 Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha 2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007; 46: 631–9.

16 Vertex Pharmaceuticals. 75% of treatment-naive patients with chronic hepatitis C achieve SVR (viral cure) with telaprevir-based treatment in Phase 3 trial. Press release, 25 May 2010.

17 Vertex Pharmaceuticals. Phase 3 ILLUMINATE Study supports 24-week telaprevir-based therapy within a response-guided regimen for people with hepatitis C who had not received prior treatment. Press release, 10 August 2010.

18 Poordad F, McCone J, Bacon BR, et al. Boceprevir combined with peginterferon alfa-2b/Ribavirin for treatment-naïve patients with hepatitis C virus genotype. 1: SPRINT-2 final results. Hepatology 2010; 52: 107A.

Source

The role of triple therapy in HCV genotype 1-experienced patients

Figure 1. PROVE 3 study design in prior non-responders and relapsers. PEG-IFN, peginterferon; RBV, ribavirin; TVR, telaprevir. Adapted from McHutchison et al. (9).

Strict stopping rules were used to minimize the development of viral resistance and exposure to therapy in case of no response. Thus, in patients treated with telaprevir, HCV RNA was required to be undetectable by week 4 in order to continue treatment. The final results of the study are shown in Figure 2.

Figure 2. Final results of PROVE 3 in prior non-responders and relapsers. P, PEG-IFN; PEG-IFN, peginterferon; R, RBV; RBV, ribavirin; T, telaprevir. Adapted from McHutchison et al. (9).

Prior relapsers had the best chance of achieving SVR, with a rate of 76% in those treated with 24 weeks of triple therapy, followed by 24 weeks of dual PEG-IFN and RBV (total duration=48 weeks) (9). The SVR rate in patients treated with only 12 weeks of triple therapy and an additional 12 weeks of dual combination therapy (total duration=24 weeks) was 69%. Prior non-responders had substantially lower rates of SVR, although nearly 40% achieved SVR with similar regimens. Interestingly, when telaprevir and PEG-IFN were used without RBV, the rate of SVR was substantially diminished, emphasizing the importance of RBV in triple therapy combinations.

As discussed previously, the risk of virological breakthrough, defined as an increase of HCV RNA of more than one-log from baseline or to more than 100 IU/ml if previously undetectable, was more frequent in previous non-responders than previous relapsers. By week 24 of treatment, up to 13% of prior relapsers and 45% of prior non-responders had evidence of virological breakthrough (9).

Telaprevir for treatment-experienced patients: phase III results

Phase III data from the REALIZE trial of telaprevir in treatment-experienced patients have only been reported to date as a company press release (10), but we will describe it briefly to provide the most current data. Nevertheless, it must be remembered that this is a preliminary non-peer-reviewed report. The study design included triple therapy with PEG-IFN, RBV and telaprevir for 12 weeks begun simultaneously or with a prior lead-in of PEG-IFN and RBV, followed by PEG-IFN and RBV for a total of 48 weeks. In previous non-responders, the SVR rate was 86% in the combined telaprevir arms and 57% in partial responders. The SVR rate in previous null responders was only 31%, showing the differential response based on prior experience with dual combination therapy.

Boceprevir for treatment-experienced patients

Full results of a comparable phase II study with boceprevir in treatment-experienced patients have not been reported. However, data from the Sprint-1 study of treatment-naïve patients suggest that the protease inhibitor boceprevir also benefited patients with a poor early response to PEG-IFN and RBV (11). The study design of Sprint-1, and subsequent phase III studies with boceprevir, used a lead-in phase of treatment for 4 weeks with PEG-IFNα-2b+RBV, followed by the addition of boceprevir. Kwo et al. (11) performed a retrospective analysis of patients based on the HCV RNA response during these first 4 weeks of dual combination therapy. Patients with less than a one-log decrease in viraemia by week 4 had only a 24% rate of SVR when treated with PEG-IFN and RBV alone, while those patients who received boceprevir at week 4 subsequently achieved an SVR of 62% (Fig. 3).

Figure 3. SPRINT 1: analysis of virological response and sustained virological response. P, PEG-IFN; R, RBV; T, telaprevir. aOne patient who was positive at week 24 became undetectable at week 30 onwards. bTwo patients were missing polymerase chain reaction (PCR) at week 24, but later had detectable PCR. Adapted from Kwo et al. (11). Presented at: AASLD; 30 October–3 November 2009, Boston, MA, USA.

It should be noted that this analysis did not include non-responders who had completed a previous full course of treatment. Nevertheless, the strong association of treatment failure with null response during the first 4 weeks of antiviral therapy suggests that these results are of interest.

RESPOND-2 is a recent phase III trial reported at the 2010 AASLD in non-responders and relapsers treated with boceprevir (12). The three-arm study compared a response-guided regimen including boceprevir to a fixed-duration 48-week triple regimen vs 48 weeks of PEG-IFN and RBV. Top-line results indicate that 75% of prior relapsers and 52% of prior non-responders treated with a fixed triple therapy boceprevir regimen achieved SVR. Relapsers and non-responders in the response-guided arm also had significant SVR rates of 69 and 40% respectively (12).

Considerations for the selection of candidates for triple therapy

Recommendations for the use of protease inhibitor triple therapy combinations are still evolving and will be dependent upon rigorous peer-reviewed analyses of phase III clinical trial data, as well as the interpretation and recommendations of various pharmaceutical regulatory agencies worldwide, such as the US Food and Drug Administration and the European Medicines Agency. Nevertheless, currently available data clearly show that triple therapies including a protease inhibitor provide exciting new therapeutic options for treatment-experienced individuals. These therapies will be most useful in prior virological relapsers, although many prior non-responders, particularly partial responders, will achieve successful viral eradication with triple therapies. The benefits of these novel treatments for each individual patient must be weighed against the side effects, cost and potential of developing viral resistance.

Conflicts of interests

Dr Fried is funded, in part, by K24 DK066144, NIH Mid-Career Mentoring Award. Dr Fried serves as a consultant for and/or receives research grants from Genentech, Vertex, Merck, Tibotec, Bristol Myers Squibb, Anadys. He is a consultant and stockholder of Pharmasset.

References

1 Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: 1335–74.

2 Fried MW, Hadziyannis S, Shiffman ML, Messinger D, Zeuzem S. Rapid virological response is the most important predictor of sustained virological response across genotypes in patients with chronic hepatitis C virus infection. J Hepatol 2010 (in press).

3 Ferenci P, Shiffman ML, Fried MW, et al. Early prediction of response to 40KDA peginterferon alfa-2a (PEGASYS) plus ribavirin in patients with chronic hepatitis C. J Hepatology 2005; 43: 425–33.

4 Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399–401.

5 Thompson AJ, Muir AJ, Sulkowski MS, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2010; 139: 120–9.e118.

6 Urban TJ, Thompson AJ, Bradrick SS, et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology 2010; 52: 1888–96.

7 Honda M, Sakai A, Yamashita T, et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology 2010; 139: 499–509.

8 Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007; 46: 631–9.

9 McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 362: 1292–303.

10 Anonymous. Vertex press release: REALIZE study. 2010.

11 Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 376: 705–16.

12 Bacon BR, Gordon SC, Lawitz EJ, et al. HCV respond-2 final results: high sustained virological response among genotype 1 previous non-responders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus pegintron(peginterferon alfa-2a)/ribairinv. Hepatology 2010; 52: 430, (abstract).

Source

San Francisco Hepatitis C Task Force Releases Recommendations for Fighting Epidemic

For immediate release

January 24, 2011 - The San Francisco Hepatitis C Task Force today released a report expressing grave concern about the hepatitis C epidemic in the City and outlining a series of recommendations for the Mayor and Board of Supervisors to mount a comprehensive effort to fight the disease. The report, entitled "Recommendations for Strategically Addressing Hepatitis C in San Francisco" is the result of a year-long process by the Task Force to identify gaps to addressing hepatitis C in San Francisco and create a set of strategic directions for San Francisco to have an immediate impact in the following areas of hepatitis C: Research and Surveillance; Prevention, Education, Awareness and Testing; Care and Treatment; and Public Policy. The report can be viewed at http://hepcsf.org/uploads/Recommendations_Document.pdf.

Some recommendations in the document include: establishing a hepatitis C coordinator position at the San Francisco Department of Public Health; ensuring full access to hepatitis C treatment and care through Healthy San Francisco; developing citywide educational/awareness campaigns; and creating a pilot legal supervised injection facility as part of a comprehensive hepatitis C prevention strategy. The report is dedicated to the memory of Randy Allgaier, who served as the Task Force's co-chair until his untimely death in November, 2010.

"This report highlights significant gaps in services for people like me living with hepatitis C and others at risk of infection," said Dominique Leslie, Task Force Co-Chair. "We urge Mayor Lee and the Board of Supervisors to take swift action to implement our recommendations."

The Task Force was convened in September, 2009, by then-Mayor Gavin Newsom and includes over 30 advocates, medical and social service providers, public health officials, and people living with hepatitis C. The group was formed in response to growing concern about the hepatitis C epidemic in the City. There are an estimated 12,000 San Franciscans infected with hepatitis C, with most not aware of their status. The disease disproportionately affects African-Americans, Latinos, veterans, people involved with the criminal justice system, injection drug users, men who have sex with men, people with HIV, immigrants, and low-income people. Hepatitis C can lead to liver disease, cirrhosis, liver cancer, liver failure and death. In January of 2010, the Institutes of Medicine (IOM) released a national report highlighting the severity of the hepatitis B and C epidemics in the United States and calling on public officials to participate in efforts to prevent, control, and care for the diseases.

"Hepatitis C is a growing epidemic that puts a significant burden on our public health and medical systems," said Todd Frederick, M.D., of California Pacific Medical Center Department of Transplantation and Task Force member. "The lifetime cost of treating one person with hepatitis C is estimated to be between $100,000 and $300,000. Those who go untreated face increased risks of developing cirrhosis and liver cancer, and the cost for a liver transplant, for which HCV is the leading cause, is estimated at $500,000. By implementing the Task Force's recommendations, San Francisco has a unique opportunity to prevent new infections and save money for the City, provide care and treatment for those living with hepatitis C, prevent long-term complications of the disease and be a leader in the national fight against this disease."

The San Francisco Hepatitis C Task Force will continue as a community coalition focused on advocating for full implementation of all recommendations and educating public officials, medical and social service providers, at-risk communities, and the general public about hepatitis C and its impact on San Francisco. For more information about the Task Force, visit www.hepcsf.org.

Contact: Ryan Clary, 415-235-8593 (cell), rclary@projectinform.org Laura Thomas, 415-241-9800, lthomas@drugpolicy.org

Source

January 26, 2011

Anadys Initiates Dosing in Phase IIb Study of ANA598

SAN DIEGO, Jan. 26, 2011 /PRNewswire/ -- Anadys Pharmaceuticals, Inc. (Nasdaq: ANDS) announced today that dosing has begun in the Phase IIb study of ANA598 in combination with pegylated interferon and ribavirin in hepatitis C patients. ANA598, the Company's direct-acting antiviral, is being tested in both treatment-naive patients and patients who failed a prior course of HCV therapy with interferon and ribavirin. Approximately 275 patients are expected to be enrolled in the study. The primary endpoint of the study is Sustained Virological Response 24 weeks after patients complete treatment, known as SVR24.

The Company expects to receive Week 8 antiviral response data for treatment-naive patients by the end of the second quarter of 2011, Week 12 antiviral response data for treatment-experienced patients in the third quarter of 2011 and Week 24 antiviral response data for both groups in the fourth quarter of 2011.

About Anadys

Anadys Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to improving patient care by developing novel medicines for the treatment of hepatitis C. The Company believes hepatitis C represents a large unmet medical need in which meaningful improvements in treatment outcomes may be attainable with the introduction of new medicines. Anadys is conducting a Phase IIb study of ANA598, the Company's DAA, added to current standard of care for the treatment of hepatitis C. The Company is also preparing to resume clinical development of ANA773, the Company's oral, small-molecule inducer of endogenous interferons that acts via the Toll like receptor 7, or TLR7, pathway in hepatitis C.

Safe Harbor Statement

Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to Anadys' expectations regarding the timing of receipt of data from the study and the ability to achieve the primary endpoint of the study. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause Anadys' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements. For example, the results of preclinical and early clinical studies may not be predictive of future results, and Anadys cannot provide any assurances that ANA598 will not have unforeseen safety issues, will have favorable results in ongoing or future clinical trials or will receive regulatory approval. In addition, Anadys' results may be affected by competition from other biotechnology and pharmaceutical companies, its effectiveness at managing its financial resources, its ability to enter into transactions around its product candidates, its ability to successfully develop and market products, difficulties or delays in its non-clinical studies or clinical trials, difficulties or delays in manufacturing its clinical trials materials, the scope and validity of patent protection for its products, regulatory developments and its ability to obtain additional funding to support its operations. Risk factors that may cause actual results to differ are more fully discussed in Anadys' SEC filings, including Anadys' Form 10-Q for the quarter ended September 30, 2010. All forward-looking statements are qualified in their entirety by this cautionary statement. Anadys is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.

SOURCE Anadys Pharmaceuticals, Inc.

RELATED LINKS
http://www.anadyspharma.com/

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HIV+ Liver Cancer Patients Less Likely to Get Transplant

But overall survival in those who received donor organ same as for other patients, study finds

Posted: January 26, 2011

WEDNESDAY, Jan. 26 (HealthDay News) -- HIV-infected patients with liver cancer who are waiting for a liver transplant are more likely to drop off the transplant waiting list than other patients, a new study has found.

But the researchers also found that the overall survival and cancer recurrence-free survival of HIV-infected patients after a liver transplant is the same as other patients.

This finding is especially important because in an era when more HIV patients survive with the use of highly active antiretroviral therapy, end-stage liver disease has now become the main cause of death among HIV patients who are also infected with chronic hepatitis B virus or hepatitis C virus, according to background material in the study. In addition, studies have shown that one-fourth of liver-related mortality in HIV-positive patients is attributable to liver cancer.

In the new study, French researchers analyzed data from 21 HIV-positive and 65 HIV-negative patients with liver cancer who were placed on a liver transplant list between 2003 and 2008. The drop-out rate from the waiting list was 23 percent for the HIV-positive patients and 10 percent for those without HIV, the investigators found.

Among HIV-infected patients, the drop-out factor was related to the patients' alpha-fetoprotein (AFP) levels. Previous research indicates that a greater than 15 microgram per liter (mcg/L) increase per month in a patient's AFP levels while on a liver transplant waiting list is a major predictive risk factor for liver cancer recurrence after a transplant.

Patients with HIV who dropped off the list had much higher AFP levels than those who eventually received a liver transplant -- 98 mcg/L versus 12 mcg/L, respectively. This large degree of difference in AFP levels was not found in HIV-negative patients -- 18 mcg/L for those who dropped off the list versus 13 mcg/L for those who underwent a liver transplant.

"Liver transplantation is the optimum treatment for [liver cancer] and can also be considered for controlled HIV-positive patients with liver cancer," lead author Dr. Rene Adam, from Hospital Paul Brousse, said in a journal news release. "Our study showed that HIV infection impaired the results of liver transplantation on an intent-to-treat basis but exerted no significant impact on overall survival and recurrence-free survival following transplantation."

The researcher also said the study confirmed the importance of AFP levels.

"There is clearly a critical need for more effective neoadjuvant therapy in HIV-positive patients with [liver cancer]; however there are no objective arguments to contraindicate liver transplantation in this group if strict criteria are used for selection and patients are closely monitored until surgery," Adam concluded in the news release.

The study findings were released online in advance of publication in the February print issue of the journal Hepatology.

Source

Also See: Survival following transplant surgery for liver cancer not impacted by HIV-positive status

Impact of a sustained virological response on the long-term outcome of hepatitis C

Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 18–22, January 2011

Alfredo Alberti

Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02378.x
© 2011 John Wiley & Sons A/S

Author Information
Department of Histology, Microbiology and Medical Biotechnologies, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy

* Correspondence: Correspondence Prof. Alfredo Alberti, Department of Histology, Microbiology and Medical Biotechnologies, Venetian Institute of Molecular Medicine, University of Padova, Via Orus 2, 35100 Padova, Italy Tel: +39 049 821 2293 Fax: +39 049 821 1826 e-mail: alfredo.alberti@gmail.com

Keywords:
cirrhosis progression; decompensation; fibrosis; HCC; modelling; natural history; outcomes; remission

Abstract

A sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA 24 weeks after withdrawal from therapy (SVR-24w), is the primary endpoint of antiviral therapy in chronic hepatitis C. There is solid evidence that patients who reach this target will remain virus free during long-term follow-up, with a risk of late HCV recurrence of <2% in published series using the most stringent criteria for assessing the virological response during and after antiviral therapy. Long-term observational studies indicate that SVR-24w has a profound impact on the natural course of chronic hepatitis C in relation to biochemical and histological remission of liver disease and improvement in quality of life. The effects of successful antiviral therapy on clinical endpoints such as the development of end-stage liver disease, its severe complications and liver-related mortality have been more difficult to ascertain because of the heterogeneity of the initial staging and rate of progression of chronic hepatitis C. However, most available data suggest that SVR following antiviral therapy reduces the risk of progression to cirrhosis and may prevent the development of severe liver complications and improve survival, at least in successfully treated patients who have already progressed to significant liver fibrosis or early cirrhosis. Outcome modelling suggests that these effects might also include HCV patients treated with milder forms of liver damage.

The primary endpoint of antiviral therapy for chronic hepatitis C is achieving sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA in serum 24 weeks after stopping antiviral therapy (SVR-24w). This is the endpoint used in all clinical trials to assess therapeutic interventions as well as by clinicians treating patients. This is because a large body of evidence exists that SVR-24w is an excellent surrogate endpoint to identify a permanent virological cure in most patients, with a clear clinical benefit in many of them. While it has been fairly easy to show that SVR-24w is associated with an extremely low risk of persistent HCV or recurrence during longer follow-up, data on the impact of SVR for more specific clinical endpoints have been limited by the heterogeneity of the initial presentation and rate and speed of chronic hepatitis C disease progression.

It is clear from studies on the natural history of HCV that a minority of patients with chronic infection develop significant life-long clinical complications, and it is also well known that current clinical practice has extended the indication to start antiviral therapy to patients with the mild or moderate hepatitis C, whose risk of progression is often difficult to define. When these patients receive antiviral therapy, data show that SVR improves quality of life and reduces the risk of histological progression. Although there is no direct evidence, outcome modelling suggests that there may be significant effects on clinical complications and survival in a subgroup of patients at risk of more rapid disease progression. On the other hand, solid evidence shows that the risk of developing end-stage liver disease, portal hypertension and hepatocellular carcinoma (HCC) is reduced in patients with more advanced liver disease or cirrhosis who achieve SVR with antiviral therapy.

In this chapter, we briefly discuss the data on the impact of SVR on long-term HCV eradication as well as on biochemical, histological and clinical outcomes in patients with hepatitis C depending on the phase of liver disease when therapy was begun.

Sustained virological response and long-term eradication of hepatitis C virus

There is good evidence that HCV permanently disappears from serum when antiviral therapy is successful. Most experts consider this to be the expression of complete and permanent viral eradication, while data on a persistent occult form of HCV in the liver and/or peripheral blood mononuclear cells (PBMC) are not fully convincing. Because HCV-RNA may be negative in serum during and at the end of antiviral therapy and reactivate after treatment withdrawal in a subgroup of patients with incomplete clearance (relapsers), viral negativity must be confirmed during off-therapy follow-up to confirm a definitive cure of hepatitis C. SVR is the primary goal of antiviral therapy in chronic hepatitis C and is classically defined as the absence, by the most sensitive polymerase chain reaction assay, of HCV-RNA in serum, 24 weeks after therapy has been withdrawn (SVR-24w) (1). This has been the definition since standard interferon (IFN) monotherapy was implemented and remained valid for IFN plus ribavirin combination therapy and more recently for pegylated interferon (PEG-IFN) plus ribavirin combination regimens. The SVR-24w definition of response to therapy will be maintained when new strategies of HCV treatment, including direct antiviral agents, are introduced into clinical practice. Indeed, most published studies as well as extensive clinical experience show that an absence of HCV-RNA in serum 6 months after therapy is the best indicator of HCV clearance, whatever the HCV genotype, patient characteristics, type and duration of treatment. This has been confirmed in several studies evaluating the long-term virological profile in large cohorts of patients treated with different schedules of IFN-based therapies and tested for HCV recurrence several months or years after having achieved SVR-24w.

Recently, Welker and Zeuzem (2) reviewed available data on the rates of late virological relapse in hepatitis C patients treated with IFN (or PEG-IFN) therapy with a sustained response based on the 24 week off-therapy rule. The authors identified 44 studies, including more than 4200 patients who had been followed up to 108 months after the end of therapy. Overall, late virological relapses were rare (3%). There was considerable heterogeneity among the different studies, with some of the smaller series reporting the highest rates of HCV recurrence. On the other hand, the larger series and those with the most stringent criteria to define SVR conclude that negative HCV-RNA in serum 24 weeks after the end of therapy is associated with a durable response and no recurrence of HCV during follow-up in more than 98% of cases.

Some studies have suggested that HCV-RNA may persist in the liver and/or in PBMC in patients who achieve SVR after antiviral therapy and with undetectable HCV-RNA in serum (3, 4). The significance of these findings is uncertain but most available data suggest that they are not clinically significant, at least in the immunocompetent host.

Thus, patients achieving SVR-24w with antiviral therapy can be considered clinically cured of viral infection, with an extremely low risk of late virological recurrence. If this occurs, reinfection rather than a ‘true’ relapse could be suspected and should be evaluated carefully.

Recently, it has been proposed that a 12-week post-treatment follow-up might be as relevant as 24 weeks to determine the sustained virological response in patients with hepatitis C virus receiving PEG-IFN and ribavirin (5).

Biochemical outcomes after sustained virological response

Alanine transaminase (ALT)/aspartate aminotransferase (AST) levels markedly improve in most patients who achieve SVR with antiviral therapy and permanently normalize in many (6, 7). The mean ALT and AST activities after therapy are significantly lower than the pretreatment baseline levels even in HCV carriers who began antiviral therapy with ‘normal’ ALT levels (8). Indeed, eradication of HCV by antiviral therapy in these cases is associated with a significant improvement in liver enzyme levels, which decrease from pretreatment ‘high normal’ to post-treatment ‘low normal’ levels. These findings suggest the presence of ongoing marginal liver disease activity even in HCV carriers with ‘normal’ range ALT levels, in agreement with histological findings of inflammation and fibrosis in around 15–25% of these patients (9).

On the other hand, liver enzymes may not normalize completely in patients with cirrhosis who achieve SVR. The discrepancy between biochemical and virological outcomes does not exclude a clinical benefit and is probably a sign of profound irreversible changes in hepatocyte metabolism from advanced cirrhosis.

As a general rule, other causes of liver damage (coinfections, alcohol, drugs, metabolic abnormalities) should be investigated in patients who achieve SVR with antiviral therapy but still have elevated ALT and/or AST.

Histological outcomes after sustained virological response

Many studies have described the histological outcome following antiviral therapy for chronic hepatitis C and have clearly identified some major differences among non-responders, partial responders, relapsers and sustained responders (10–15). Although the benefit to disease activity and progression with a partial or a transient virological response remains controversial, these studies clearly confirm that SVR is associated with histological improvement in disease activity and associated fibrosis. Liver steatosis is also improved when it is directly linked to HCV as for HCV-3.

The type and degree of histological benefit after SVR is highly dependent on pretreatment activity, the stage of liver disease and the interval between end of therapy and liver biopsy. Improvement in liver inflammation is more evident when a liver biopsy is obtained years rather than months after the end of therapy. The effect of time is even more evident for the regression of liver fibrosis. Available studies indicate that liver inflammation resolves in most, if not all, patients after SVR while improvement in fibrosis (regression) is found in 25–80%, worsening (progression) in only 0–12, and 16–68% remain stable. These results are significantly different from those in patients who do not achieve SVR. Table 1 describes some studies that have evaluated histological outcome after SVR using paired liver biopsies before and at different intervals after antiviral therapy. Available cumulative data on progression to cirrhosis have indicated that the risk after 1–10 years is reduced from 7–10% in non-responders to 0.5–1% in sustained responders, although it should be emphasized that patients who achieve SVR might have a milder and less progressive form of liver disease compared with non-responders.

Reversal of histological cirrhosis has been reported in patients achieving SVR with antiviral therapy. Although in most patients the benefit was limited to regression to METAVIR stage 3, i.e. advanced fibrosis with bridging, a histological sampling error cannot be excluded, other patients have been shown to achieve more marked and permanent histological benefit with regression from signs of cirrhosis to minimal-mild fibrosis.

Recent non-invasive markers of liver fibrosis, such as the FibroTest and FibroScan, have become important new tools for the management of patients with chronic hepatitis C. Results in patients receiving antiviral therapy have confirmed a marked improvement in liver fibrosis indexes following SVR (16, 17). Further validation for the optimized use of these methods during and after antiviral therapy is ongoing in several centres.

Sustained virological response and clinical outcomes

Morbidity and mortality in chronic hepatitis C infection are mainly associated with the complications of cirrhosis and the development of HCC, as well as an increased risk in liver-related deaths. It is therefore essential to assess the impact of SVR on these clinical outcomes. Because of the heterogeneity of the clinical presentation of chronic HCV infection, the slow and unpredictable progression and the lack of longitudinal studies of adequate size and duration, the impact of antiviral therapy and SVR on liver-related complications and mortality has been difficult to determine, especially in patients with milder forms of HCV-related liver disease. Although the endpoint of SVR is clearly associated with reduced histological disease progression in these patients, there is no clear evidence that this will result in reduced morbidity and mortality. At present, many patients with mild chronic hepatitis C are treated with antiviral therapy, especially younger patients or those infected with easy to clear HCV genotypes.

High SVR rates are achieved in these patients and outcome modelling also suggests that successful antiviral therapy could reduce the clinical burden of their disease. On the other hand, there are also convincing results associating a marked improvement in quality of life with SVR after antiviral therapy. This effect is largely independent of the stage of disease when treatment is begun (18). The clinical benefit associated with HCV clearance at any stage of chronic HCV infection is supported by recent results in a large population-based survey by Omland and Krarup (19), showing that overall life-long mortality as well as liver-and HCC-related mortality were significantly lower in HCV patients who showed a clearance of viraemia than in those with chronic viraemia.

Unlike the data for patients with milder forms of chronic hepatitis C, several studies have clearly shown that antiviral therapy with SVR is associated with a marked improvement in clinical outcomes in patients with advanced fibrosis or compensated cirrhosis. Indeed, most studies show that ascites, hepatic encephalopathy, jaundice or gastrointestinal bleeding are extremely rare after SVR has been achieved. Development of hepatocellular carcinoma is also significantly reduced, but patients with cirrhosis who clear HCV during antiviral therapy are still at a risk of developing HCC. Although the risk is certainly much lower than in age/gender/race-matched patients with active disease, continued monitoring is recommended. One of the most recent reports on the impact of combination PEG-IFN and ribavirin therapy on clinical outcome and complications in patients with chronic hepatitis C and advanced fibrosis is that of Cardoso et al. (20). These authors describe long-term outcomes in 307 patients with chronic hepatitis C and advanced fibrosis (127 cases) or cirrhosis (180 cases) treated with PEG-IFN plus ribavirin and followed up for a mean 3–5 years after treatment. SVR-24w was found in 33% of the cases, with no significant differences between patients with advanced fibrosis (37%) and cirrhosis (30%). During follow-up, the incidence of liver-related complications, HCC and liver-related deaths per 100 person – years was 0.63, 1.24 and 0.61, respectively, in patients with SVR and 4.16, 5.85 and 3.66, respectively, in patients without SVR. The difference for each outcome was statistically significant (P<0.001 by log-rank test). Multivariate analysis confirmed that SVR protected against progression to liver complications, HCC and liver-related deaths, with the relative risk in the absence of SVR ranging between 3.06 and 4.73. These results confirm those of several previous studies based on cohorts of patients treated with standard IFN, standard IFN plus ribavirin or PEG-IFN plus ribavirin, showing that antiviral treatment provides a definitive clinical advantage to patients with compensated cirrhosis who tolerate treatment and achieve an SVR.

Another recent study published by Bruno et al. (21) reported the effect of antiviral therapy and SVR on portal hypertension in HCV patients with cirrhosis. The authors reported results in 218 patients with cirrhosis who were untreated or treated with IFN-α-based therapy and followed up for a median 11.4 years. All patients had compensated cirrhosis when therapy began without oesophageal varices. Endoscopic monitoring was performed at 3-year intervals. None of the patients who achieved SVR developed oesophageal varices during follow-up compared with 32% of untreated patients and 39% of treated patients who did not achieve SVR, showing that SVR clinically improved the development of portal hypertension.

In conclusion, SVR improves the clinical outcomes in patients with chronic hepatitis C and advanced fibrosis or compensated cirrhosis. On the other hand, most studies assessing whether a partial response or long-term maintenance therapy with PEG-IFN without viral eradication is beneficial have failed to demonstrate any significant improvement in clinical outcomes (22, 23).

Conflicts of interest

The author has declared no potential conflicts.

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